Objective To explore the protective effect and possible mechanism of Periplaneta americana powder on rats with spinal cord injury. Methods Forty-eight male SD rats were randomly divided into sham operation, saline,Periplaneta americana powder, and Toll-like receptor 4 (TLR4) inhibitor groups. Except for the sham operation group, a rat spinal cord hemi-transection injury model was established in the other three groups. The sham operation group received no treatment after the operation, saline and drug groups were subjected to intragastric administration of equal volumes of normal saline and Periplaneta americana powder ( 630 mg / kg ), respectively, and the TLR4 inhibitor group was administered an intraperitoneal injection of TLR4 inhibitor (3 mg / kg). On days 1, 3, 7, and 14 after the operation, the motor function of rat hind limbs was evaluated by the Basso, Beattie, and Bresnahan ( BBB) score. Histopathological changes of the spinal cord were observed by hematoxylin-eosin staining. Changes in the number of neurons were observed by immunohistochemistry. The levels of inflammatory factors IL-1, IL-6, IL-10, and TNF-α were measured by ELISA, and expression of TLR4, myeloid differentiation factor 88 (MyD88), and NF-κB p65 was detected by Western Blot. Results Compared with the sham operation group, the BBB score and number of neurons in the saline group were significantly decreased, while the degree of pathological damage, and IL-1, IL-6, TNF-α, TLR4, MyD88, and NF-κB p65 levels were significantly increased (P < 0. 05). Compared with the saline group, periplaneta americana powder and TLR4 inhibitor groups showed an increase in BBB scores and the number of neurons, and decreases in the degree of pathological damage and IL-1, IL-6, TNF-α, TLR4, MyD88, and NF-κB p65 levels (P < 0. 05). Compared with the TLR4 inhibitor group,the periplaneta americana powder group had better increases in the BBB score, number of neurons and decreases in the degree of pathological damage and expression of IL-1 and TNF-α. Conclusions Periplaneta americana powder reduces the production of inflammatory factors after spinal cord injury by inhibiting the TLR4 / MyD88 / NF-κB pathway, protects nerves,and promotes motor recovery.